Hominins likely occupied northern Europe before one million years ago

Our understanding of when hominins first reached northern Europe is dependent on a fragmented archaeological and fossil record known from as early as marine isotope stage (MIS) 21 or 25 (c. 840 or 950 thousand years ago [Ka]). This contrasts sharply with southern Europe, where hominin occupation is evidenced from MIS 37 to 45 (c. 1.22 or 1.39 million years ago [Ma]). Northern Europe, however, exhibits climatic, geological, demographic, and historical disadvantages when it comes to preserving fossil and archaeological evidence of early hominin habitation. It is argued here that perceived differences in first occupation timings between the two European regions needs to be revised in light of these factors. To enhance this understanding, optimal linear estimation models are run using data from the current fossil and artefact record. Results suggest northern Europe to have first been occupied as early as 1.16 Ma, or as late as 913 Ka. These timings could represent minimum date expectations and be extended through future archaeological and fossil discoveries

Time to publication for NIHR HTA programme-funded research: a cohort study

ObjectiveTo assess the time to publication of primary research and evidence syntheses funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme published as a monograph in Health Technology Assessment and as a journal article in the wider biomedical literature.Study designRetrospective cohort study.SettingPrimary research and evidence synthesis projects funded by the HTA Programme were included in the cohort if they were registered in the NIHR research programmes database and was planned to submit the draft final report for publication in Health Technology Assessment on or before 9 December 2011.Main outcome measuresThe median time to publication and publication at 30?months in Health Technology Assessment and in an external journal were determined by searching the NIHR research programmes database and HTA Programme website.ResultsOf 458 included projects, 184 (40.2%) were primary research projects and 274 (59.8%) were evidence syntheses. A total of 155 primary research projects had a completion date; the median time to publication was 23?months (26.5 and 35.5?months to publish a monograph and to publish in an external journal, respectively) and 69% were published within 30?months. The median time to publication of HTA-funded trials (n=126) was 24?months and 67.5% were published within 30?months. Among the evidence syntheses with a protocol online date (n=223), the median time to publication was 25.5?months (28?months to publication as a monograph), but only 44.4% of evidence synthesis projects were published in an external journal. 65% of evidence synthesis studies had been published within 30.0?months.ConclusionsResearch funded by the HTA Programme publishes promptly. The importance of Health Technology Assessment was highlighted as the median time to publication was 9?months shorter for a monograph than an external journal article

Statistical analysis of magnetic divertor configuration influence on H-mode transitions

DIII-D plasmas are compared for two upper divertor configurations: with the outer strike point on the small angle slot (SAS) divertor target and with the outer strike point on the horizontal divertor target (HT). Scanning the vertical distance between the magnetic null point and the divertor target over a range 0.10–0.16 m is shown to increase the threshold power, Pth , and edge plasma power, PLoss , for the low-to-high confinement (L–H) and H–L transitions respectively, by up to a factor of 1.4. The X-point height scans were performed at three L-mode core plasma line average electron densities, n¯e= 1.2, 2.2 and 3.6 ×1019m−3 , to investigate the density dependence of divertor magnetic configuration influence on Pth . The X-point height, Zx-pt , was further extended across the range 0.16–0.22 m with the more open HT divertor configuration, for which a clear decrease in Pth with increasing Zx-pt is observed. The dependence of Pth on divertor magnetic geometry is further investigated using a time-dependent probability density function (PDF) model and information geometry to elucidate the roles played by pedestal plasma turbulence and perpendicular velocity flows. The degree of stochasticity of the plasma turbulence is observed to be sensitive to the plasma heating rate. The calculated square of the information rate shows changes in the relative density fluctuations and perpendicular velocity PDFs begin 2–5 ms prior to the L–H transition for three plasmas; providing a crucial measurement of the dynamic timescale of external transport barrier formation. Additionally, both information length and rate provide potential predictors of the L–H transition for these plasmas

A combination of trastuzumab and BAG-1 inhibition synergistically targets HER2 positive breast cancer cells

Treatment of HER2+ breast cancer with trastuzumab is effective and combination anti-HER2 therapies have demonstrated benefit over monotherapy in the neoadjuvant and metastatic settings. This study investigated the therapeutic potential of targeting the BAG-1 protein co-chaperone in trastuzumab-responsive or -resistant cells. In the METABRIC dataset, BAG-1 mRNA was significantly elevated in HER2+ breast tumors and predicted overall survival in a multivariate analysis (HR = 0.81; p = 0.022). In a breast cell line panel, BAG-1 protein was increased in HER2+ cells and was required for optimal growth as shown by siRNA knockdown. Overexpression of BAG-1S in HER2+ SKBR3 cells blocked growth inhibition by trastuzumab, whereas overexpression of a mutant BAG-1S protein (BAG-1S H3AB), defective in binding HSC70, potentiated the effect of trastuzumab. Injection of a Tet-On SKBR3 clone, induced to overexpress myc-BAG-1S into the mammary fat pads of immunocompromised mice, resulted in 2-fold larger tumors compared to uninduced controls. Induction of myc-BAG-1S expression in two Tet-On SKBR3 clones attenuated growth inhibition by trastuzumab in vitro. Targeting endogenous BAG-1 by siRNA enhanced growth inhibition of SKBR3 and BT474 cells by trastuzumab, while BAG-1 protein-protein interaction inhibitor (Thio-S or Thio-2) plus trastuzumab combination treatment synergistically attenuated growth. In BT474 cells this reduced protein synthesis, caused G1/S cell cycle arrest and targeted the ERK and AKT signaling pathways. In a SKBR3 subpopulation with acquired resistance to trastuzumab BAG-1 targeting remained effective and either Thio-2 or BAG-1 siRNA reduced growth more compared to trastuzumab-responsive parental cells. In summary, targeting BAG-1 function in combination with anti-HER2 therapy might prove beneficial

Alternative tissue fixation for combined histopathological and molecular analysis in a clinically representative setting

Formalin is the principal tissue fixative used worldwide for clinical and research purposes. Despite optimal preservation of morphology, its preservation of DNA and RNA is poor. As clinical diagnostics increasingly incorporates molecular-based analysis, the requirement for maintaining nucleic acid quality is of increasing importance. Here we assess an alternative non-formalin-based tissue fixation method, PAXgene Tissue system, with the aim of better preserving nucleic acids, while maintaining the quality of the tissue to be used for vital existing diagnostic techniques. In this study, these criteria are assessed in a clinically representative setting. In total, 203 paired PAXgene Tissue and formalin-fixed samples were obtained. Blind-scored haematoxylin and eosin (H&E) sections showed comparable and acceptable staining. Immunohistochemistry (IHC) staining was suboptimal using existing protocols but improved with minor method adjustment and optimisation. Quality of DNA and RNA was significantly improved by PAXgene tissue fixation [RIN 2.8 versus 3.8 (p < 0.01), DIN 5.68 versus 6.77 (p < 0.001)], which translated into improved performance on qPCR assay. These results demonstrate the potential of PAXgene Tissue to be used routinely in place of formalin, maintaining adequate histological staining and significantly improving the preservation of biological molecules in the genomic era

Novel GPR34 and CCR6 mutation and distinct genetic profiles in MALT lymphomas of different sites.

Mucosa-associated lymphoid tissue (MALT) lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterized. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma. The majority of mutations in GPR34 and CCR6 were nonsense and frameshift changes clustered in the C-terminal cytoplasmic tail, and would result in truncated proteins that lack the phosphorylation motif important for β-arrestin-mediated receptor desensitization and internalization. Screening of these newly identified mutations, together with previously defined genetic changes, revealed distinct mutation profiles in MALT lymphoma of various sites, with those of salivary gland characterized by frequent TBL1XR1 and GPR34 mutations, thyroid by frequent TET2, TNFRSF14 and PIK3CD mutations, and ocular adnexa by frequent TNFAIP3 mutation. Interestingly, in MALT lymphoma of the salivary gland, there was a significant positive association between TBL1XR1 mutation and GPR34 mutation/translocation (P=0.0002). In those of ocular adnexa, TBL1XR1 mutation was mutually exclusive from TNFAIP3 mutation (P=0.049), but significantly associated with IGHV3-23 usage (P=0.03) and PIK3CD mutation (P=0.009). These findings unravel novel insights into the molecular mechanisms of MALT lymphoma and provide further evidence for potential oncogenic co-operation between receptor signaling and genetic changes.The research was supported by grants from Bloodwise (13006, 15002, 15019) UK, and Kay Kendal Leukaemia Fund (KKL582), UK. SM was initially supported by a PhD studentship from Medical Research Council, Department of Pathology, University of Cambridge and Addenbrooke’s Charitable Trust

Angioimmunoblastic T cell lymphoma : novel molecular insights by mutation profiling

Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan (n = 6) and U.K. (n = 3). We confirmed frequent mutations in TET2 (9/9), DNMT3A (3/9), IDH2 (3/9), RHOA (3/9) and PLCG1 (2/9) as recently reported by others. More importantly, we identified mutations in TNFRSF21 (1/9), CCND3 (1/9) and SAMSN1 (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators TET2 and DNMT3A occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in RHOA, PLCG1 and TNFRSF21 (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL

Angioimmunoblastic T cell lymphoma: novel molecular insights by mutation profiling

Angioimmunoblastic T cell lymphoma (AITL) originates from follicular helper T-cells and is characterised by a polymorphic infiltrate with the neoplastic T-cells forming small clusters around the follicle and high endothelial venules. Despite the recent advances in its phenotypic characterisation, the genetics and molecular mechanisms underlying AITL are not fully understood. In the present study, we performed whole exome sequencing in 9 cases of AITL from Taiwan ($\textit{n}$ = 6) and U.K. ($\textit{n}$ = 3). We confirmed frequent mutations in $\textit{TET2}$ (9/9), $\textit{DNMT3A}$ (3/9), $\textit{IDH2}$ (3/9), $\textit{RHOA}$ (3/9) and $\textit{PLCG1}$ (2/9) as recently reported by others. More importantly, we identified mutations in $\textit{TNFRSF21}$ (1/9), $\textit{CCND3}$ (1/9) and $\textit{SAMSN1}$ (1/9), which are not yet seen or strongly implicated in the pathogenesis of AITL. Among the pathogenic mutations identified in AITL, mutations in DNA methylation regulators $\textit{TET2}$ and $\textit{DNMT3A}$ occur early in hematopoietic stem cells as shown by previous studies, and these genetic events enhance the self-renewal of hematopoietic stem cells, but are unlikely to have any major impact on T-cell differentiation. Mutations in $\textit{RHOA}$, $\textit{PLCG1}$ and $\textit{TNFRSF21}$ (DR6), which encode proteins critical for T-cell biology, most likely promote T-cell differentiation and malignant transformation, consequently generating the malignant phenotype. Our findings extend the molecular insights into the multistage development of AITL.The research was supported by grants from Kay Kendall Leukaemia Fund (KKL582), and Bloodwise, U.K. (13006). SZ was supported by a scholarship from the Master Hsingyun Cultural and Education Foundation. We thank Wenhan Deng for DNA preparation in some of the cases used in this study